STEAP1 Regulated By EIF4E Promotes The Progression Of Gastric Cancer

Objective:As a kind of malignant tumor,gastric cancer patients often occurs metastasis.Peritoneal metastasis is the most common,while its exact mechanism is still unclear.Peritoneal metastasis of gastric cancer is considered to be a difficult problem in the treatment of gastric cancer.In addition,there are no standard strategies to treat peritoneal metastasis of gastric cancer.Hence,it is necessary to understand the modulation of peritoneal dissemination in gastric cancer.The purpose of this study was to investigate the regulatory mechanism of the expression of STEAP1,a critical protein during peritoneal dissemination,and its effect on the progression of gastric cancer.Methods:We harvested the cancer and paracancerous tissues from 20 peritoneal dissemination patients with gastric cancer,and separated the polyribosomes from the two kinds of tissue samples.The qRT-PCR was utilized to identify the differential expression profile of genes(related to epithelial to interstitial transformation(EMT))using the cancer and paracancerous tissues.Proteasome inhibitor MG-132 was used to treat HMrSv5 and MKN45 cells to inhibit proteasome degradation.Luciferase assay was used to study the translation regulation mechanism of STEAP1.CGP57380,a MNK inhibitor,was used to treat MKN45 cells to inhibiteIF4 E phosphorylation.Transwell cell migration and invasion detected the ability of cell invasion and migration in MNK45 cells.The tumor growth ability was detected by xenogeneic tumor assay in nude mice.Results:By comparing the difference of polyribosomes from tumor tissue and paracancerous tissue in peritoneal dissemination patients with gastric cancer,we identified 49 differentially expressed EMT-related genes in polyribosomes from tumor tissue,among which 30 genes were up-regulated and 19 genes were down regulated.STEAP1 was the most up-regulated gene.STEAP1 is the most significant up-regulated gene in tumor tissue among them.In gastric cancer patients with peritoneal metastasis,the protein expression of STEAP1 was increased,both in men and women.However,there was no significant difference in the mRNA expression of STEAP1 between men and women with peritoneal metastasis of gastric cancer.The degradation of proteasome did not contribute to the phenomenon.Luciferase assay results showed that STEAP1 mRNA is being regulated at the levels of 5’ 7mG cap-dependent translational initiation.Western blot and QRT PCR further proved that P-eIF4 E is regulating translation initiation of STEAP1 in the MKN45 cells.The overexpression of STEAP1 promoted the migration and invasion of gastric cancer cells,as well as the growth and peritoneal metastasis of xenografts tumor.Conclusion:1.We identified 49 differentially expressed EMT-related genes in polyribosomes from tumor tissue of peritoneal dissemination patients with gastric cancer,among which 30 genes were up-regulated and 19 genes were down regulated.STEAP1 was the most up-regulated gene.2.The expression of STEAP1 was up-regulated in gastric cancer with peritoneal metastasis.3.The expression of STEAP1 is regulated at translational initiation.4.The up-regulation of STEAP1 depends on the regulation of eIF4 E phosphorylation.5.High expression of STEAP1 promotes the migration and invasion of gastric cancer cells and tumor growth in vivo.